tbuckley/cabot-search huggingface dataset:
STEM-07. DEFINING THE ROLE OF HUMAN ENDOGENOUS RETROVIRUS-K (HML-2) IN THE GLIOBLASTOMA STEM-CELL NICHE
Authors: Ashish Shah, Sarah Rivas, Tara Doucet-Ohare, Vaidya Govindarajan, Catherine DeMarino, Leo Ampie, Yeshavanath Banasavadi-Siddegowda, Dragan Maric, Marta Garcia-Montojo, Rob Suter, Myoung-Hwa Lee, Stuart Walbridge, Kareem Zaghloul, Joseph Steiner, Kory Johnson, Mark Gilbert, John Heiss, Avindra Nath
Journal: Neuro-Oncology (2022)

Abstract Human Endogenous Retrovirus (HERV) are ancestral viral relics that comprise nearly 8% of the human genome. Although silenced in normal tissues, the most recently integrated provirus HERV-K (HML-2) can be pathologically reactivated in certain cancers. Here, we report pathological expression of HML-2 transcripts in human malignant gliomas in cerebrospinal fluid (HERV-K DNA/RPP30=35.2±8.8 vs 23.1±6.7, n=18, p=0.02) and tumors (HERV-K RNA/HPRTmean=1.15±0.2 vs. 0.5±0.2, p=0.01, n=20) compared to epilepsy controls. Aberrant HML-2 expression corresponded to a unique stem-cell niche using multivoxel automated segmentation. Using a tailored single-cell RNA sequencing pipeline to detect retrotransposons, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor-like cells that can drive cellular plasticity (ANOVA, multiple-testing correction, p&amp;lt; 0.001). Using CRISPR technology, we demonstrate that HML-2 is critical to maintenance of glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models (OS: 26 days vs. 18.6, p=0.0008, n=20). Downregulation of HERV-K using CRISPRi reduces the glioblastoma neurosphere formation (2-way ANOVA, p&amp;lt; 0.0001). and HERV-K env, Polymerase, OCT4 and Nestin transcripts (2-way ANOVA p&amp;lt; 0.001). Using Chromatin Immunoprecipitation, we determined that this interaction in gliomas is likely mediated by the nuclear transcription factor OCT4 which binds to an HML-2 specific Long-Terminal Repeat (LTR5Hs). Moreover, using Transmission Electron Microscopy, we discovered that some glioma stem-cells form immature retroviral virions in glioblastoma. Inhibiting HML-2 expression with nucleoside reverse transcriptase inhibitors reduces extracellular reverse transcriptase (One-way ANOVA, p&amp;lt; 0.05), tumor viability (IC50=75.8-123.1 uM), and pluripotency (One-way ANOVA, p&amp;lt; 0.01). Our results suggest that HML-2 is overexpressed in the cancer stem-cell niche of glioblastoma. Since persistence of glioblastoma stem-cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target in glioblastoma.
NIMG-13. DEEP LEARNING-BASED AUTOMATIC DETECTION AND SEGMENTATION OF BRAIN METASTASES FOR STEREOTACTIC ABLATIVE RADIOTHERAPY USING BLACK-BLOOD MAGNETIC RESONANCE IMAGING
Authors: Tae Hyung Kim, Sang Kyun Yoo, Hojin Kim, Jin Sung Kim, Hong In Yoon
Journal: Neuro-Oncology (2022)

Abstract PURPOSE/OBJECTIVES Stereotactic ablative radiotherapy (SABR) is becoming popular in the treatment of Brain metastases (BM). However, detection and manual delineation of BM are labor-intense processes, and normal blood vessels are occasionally mistaken for metastatic lesions. In this study, we investigated the efficacy and accuracy of a deep learning (DL) model for the detection and segmentation of BM using black-blood (BB) magnetic resonance imaging (MRI). MATERIALS/METHODS The BB MRI data of 48 patients with 806 BMs were collected to train and validate the DL model. Since MRI data have an inconsistent intensity scale across the patients, we applied piecewise linear histogram matching algorithm, also called the Nyul normalization. To deal with bias corruption in the patient, N4 bias field correction was applied. The modified U-Net was implemented to automatically detect and segment BMs. The detection performance was measured with sensitivity and average false positives and the segmentation performance was measured with the dice score (DSC). RESULTS Twelve patients with 132 BMs were randomly selected as the test-set for evaluating our trained model. In the test-set, 19.2% BMs had a volume of &amp;lt; 0.02 cc, max volume of 16.642 cc, min volume of 0.009 cc, median volume of 0.071 cc, and mean volume of 1.158 cc. The sensitivity was 96.87% and average false positives were 0.2. We consider &amp;lt; 0.02 cc volume as the small volume. 100% sensitivity for BMs with volumes ≥ 0.02 cc, and 84.6% sensitivity for BMs with volumes &amp;lt; 0.02 cc volume. The DSC was 86.27 (range, 77-91.2). CONCLUSIONS Our model can detect and segment BMs on BB MRI data with good detection and segmentation performance. Further study is on a way to generate a synthetic BB image from the T1-Gd image by applying this model.
BIOM-08. IL13RA2 AS A LIQUID BIOPSY BIOMARKER FOR NERVOUS SYSTEM TUMORS
Authors: Vladimir Khristov, Darya Nesterova, Neel Patel, Nataliya Smith, Ganesh Shenoy, Brad Zacharia, Kimberly Harbaugh, Elias Rizk, James Connor
Journal: Neuro-Oncology (2022)

Abstract While tumors of the nervous system (NS) are rare, they contribute to significant morbidity and mortality. Despite advances in imaging technology, initial diagnosis and characterization of treatment response remains problematic for devastating tumors such as glioblastoma (GBM). A liquid biopsy can provide a minimally-invasive and serial source of biomarkers to supplement current diagnostic methods. Here, we utilize a unique characteristic of NS tumors including GBM and schwannoma/neurofibroma – the overexpression of the a2 variant of the IL-13 receptor which is not detectable in normal tissue. Previously, we have shown that IL13Ra2 is elevated in the plasma of some GBM patients above baseline levels. We hypothesize that the presence of circulating IL13Ra2 not only predicts the level of this receptor in the tumor tissue, but also has clinical prognostic value. Here, we used ELISA to measure the plasma levels of IL13Ra2 in the GBM (n=77) and schwannoma/neurofibroma (n=15) patients and correlated these levels to tumor levels, diagnosis, and clinical characteristics. We have demonstrated that elevated levels of plasma IL13Ra2 correlated with tumor presence compared to non-tumor controls for both GBM and schwannoma/neurofibroma patients, indicating this biomarker’s diagnostic utility. Further, for both GBM and schwannoma/neurofibroma patients the plasma concentration of IL13Ra2 is correlated to its tumor concentration, indicating that sampling patient plasma could provide insight into the tumor’s composition. Finally, elevated levels of IL13Ra2 protein in the tumor and plasma of GBM patients predicted longer patient survival. These exciting findings lay the groundwork for a plasma-based NS tumor liquid biopsy.
TMET-31. CHOLESTEROL ESTERIFICATION IN A PATIENT WITH DIFFUSE ASTROCYTOMA PROGRESSING TO GLIOBLASTOMA
Authors: Omkar Ijare, David Baskin, Kumar Pichumani
Journal: Neuro-Oncology (2022)

Abstract Metabolic profiles of diffuse astrocytoma and recurrent tumor tissues were compared in a patient with diffuse astrocytoma who showed tumor recurrence and progressed to glioblastoma (GBM). The patient presented with a diffuse infiltrating tumor and was operated in April 2018. The pathology report showed that the tumor was a diffusely infiltrating astrocytoma with Ki-67 of 5% (WHO Grade II). In addition, the molecular testing results indicated that the tumor was IDH1wt with TERTp mutation and showed an indeterminate MGMT promoter status. Given diffuse brain involvement and IDH1wt status, an aggressive behavior was suggested for this tumor. After ~3.5 years (January 2022), the MRI examination showed tumor recurrence and the patient underwent craniotomy for the resection of the recurrent tumor. The pathology report showed a high-grade glial neoplasm composed of ovoid tumor cells with nuclear pleomorphism (GBM, WHO Grade IV). We collected the tumor specimens from both surgeries and compared the metabolic profiles using 1H NMR spectroscopy. The tumor specimens were extracted using methanol-chloroform (2:1 ratio) extraction-method. The methanol-layer of the recurrent tumor showed decreased levels of N-acetylaspartate (NAA) and myo-inositol, and the elevated levels of phosphocholine (PC) and glycine, compared to the diffuse astrocytoma. Decreased NAA and elevated PC and glycine are metabolic features of high-grade gliomas, suggesting progression of the low-grade astrocytoma to GBM. The chloroform-layers of both tumors showed the presence of cholesterol; however, cholesteryl ester (CE) was detected only in the recurrent tumor (GBM). The ratio of CE to cholesterol was 0.44, suggesting that 44% of cholesterol pool was esterified in GBM. Cholesterol esterification is dysregulated in GBM and targeting this metabolic pathway using AcylCoA:cholesterol acyltransferase (ACAT) inhibitors would be promising in the treatment of GBM and astrocytomas with TERTp mutation which transform to GBM.
TMIC-04. TARGETING AN ECM PROTEIN INVOLVED IN BREAST CANCER BRAIN METASTASES WITH AN ONCOLYTIC HSV-1
Authors: Kimberly Rivera-Caraballo, Ji young Yoo, Bangxing Hong, Balveen Kaur
Journal: Neuro-Oncology (2022)

Abstract The beta-1 subunit of integrins (CD29) is important for cell-extracellular matrix interactions. CD29 expression is increased in breast cancer cells, and it promotes their invasion, migration, and intravasation, all of which can result in breast cancer brain metastasis (BCBM). While CD29 expression can be correlated to poor prognosis of breast cancer patients, the median survival of BCBM patients predicted to have better prognosis is 36 months. Despite current BCBM treatments such as craniotomy, reaching the metastatic site is often challenging. Modified viral vectors, such as oncolytic herpes simplex virus (oHSV), have been clinically approved for the treatment of malignant melanoma and brain tumors, as they infect and selectively kill tumor cells. Previously, we identified that combination of oHSV and humanized CD29 blocking antibody (OS2966, aCD29) enhanced viral replication by reducing antiviral immune response, increased tumor cell killing, and rendered survival benefit to tumor bearing mice with intra-tumoral, but not systemic, oHSV administration. These findings suggested that the antitumor efficacy of the therapeutic combination required intratumoral delivery of anti-CD29, since the antibody could not penetrate the blood brain barrier and reach intracranial tumors. To overcome this, we report the generation of an oHSV encoding the scFv-Fc fragment of this antibody (HSV-aCD29), which retains its oncolytic function, and evaluate the impact of HSV-aCD29 on the CD29 downstream signaling. We will further characterize the safety, antitumor efficacy, and assess the immune response to HSV-aCD29 in vitro and in vivo. We anticipate that compared to our control virus, HSV-aCD29 will block CD29 activity which will reduce antiviral immune responses and enhance tumor cell lysis, thus improving oHSV efficacy. Together, this study proposes the blockade of CD29 with the targeted delivery of a CD29 blocking antibody mediated by a novel oHSV as a potential synergistic therapy against BCBM.
RADT-29. THE IMPACT OF TUMOR LOCATION AT THE SKULL BASE ON RADIATION NECROSIS IN PATIENTS UNDERGOING STEREOTACTIC RADIOSURGERY: AN ANALYSIS OF 205 PATIENTS
Authors: Johannes Kerschbaumer, Matthias Demetz, Aleksandrs Krigers, Meinhard Nevinny-Stickel, Claudius Thomé, Christian Freyschlag
Journal: Neuro-Oncology (2022)

Abstract Background Skull base (SB) surgery and radiosurgery (SRS) are an interdisciplinary concept and represent an individualized treatment option for various skull base tumors. Radiation necrosis (RN) is a possible sequela of SRS, but despite few accepted risk factors, there is very limited data on the influence of tumor location. The aim of this study was to assess tumor location in correlation to the development of radiation necrosis for skull-base tumors. METHODS All patients treated with radiosurgery for meningioma, vestibular schwannoma and other benign neoplasms between January 2004 and November 2020 were retrospectively evaluated. The clinical, imaging and medication data were gained from the patients’ charts. The diagnosis of RN was established retrospectively using imaging parameters. Patients with tumors located at the skull base were compared to patients with tumors of other location. RESULTS A total of 205 patients could be included in this study. 157 neoplasms (76.6%) were localized at the SB, while the remaining 48 (23.4%) were non-SB. 32 (15.6%) of all patients developed RN after median 10 (IqR 5-12) months during a median follow-up of 24 (IqR 6-62) months. SB-tumors showed a significantly lower risk of radiation necrosis with a Hazard Ratio (HR) of 0.252, p &amp;lt; 0.001, independently of the applied radiation dose. Furthermore, higher radiation doses had a significant impact on the occurrence of RN (HR 1.372, p = 0.002). No significant difference could be shown for age, previous resection or previous radiosurgery. Administered dose of dexamethasone did not correlate with the risk of radiation necrosis. CONCLUSION The risk for development of RN for SB-tumors appears to be low. No difference between recurrent and newly diagnosed tumors was found, which may underpin the value of radiosurgical treatment for patients with recurrent SB-tumors. For extensive tumors of the SB, combinations of surgery and radiosurgery represents a valuable approach.
PATH-21. INVESTIGATING CHANGES IN IDH MUTATION STATUS AT GLIOMA RECURRENCE
Authors: Mathew Voisin, Chloe Gui, Gelareh Zadeh
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Isocitrate dehydrogenase (IDH) mutation status is a key diagnostic and prognostic feature of gliomas. It is thought to occur early in glioma tumorigenesis and remains stable over time. We investigated our tumour bank to identify patients where IDH mutation status changed after glioma recurrence. METHODS We identified four patients with immunohistochemistry-recorded IDH mutation statuses that conflicted between multiple tumour samples taken over time. Tissue samples from the tumour bank were analyzed using methylation profiling and Sanger sequencing of IDH1 and IDH2 to verify IDH status. RESULTS In all four instances, we found that IDH mutation status in fact remained stable, and there were reasonable explanations as to why mutation status was misinterpreted. One tumour had a non-canonical IDH2 R172K mutation that is not routinely tested for. Two patients had perilesional samples, revealed by methylation profiling to contain a mixture of tumour and normal brain. One patient had a IDH wildtype sample with a methylation profile consistent with reactive brain tissue rather than tumour. CONCLUSIONS All four cases of IDH mutation change at glioma recurrence were due to either misinterpreting perilesional or reactive tissue as tumour or overlooking a non-canonical mutation. This finding supports the concept that IDH mutation is a fixed characteristic of gliomas and highlights the importance of accurate surgical biopsy and molecular testing at initial diagnosis.
DDEL-12. QUADRUPLE CARBON DOT NANO MODEL FOR ENHANCED TUMOR TARGETING AND DUAL DRUG DELIVERY FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Regina Graham, Emel Kirbas Cilinger, Sajini Hettiarachchi, Yiqun Zhou, Braulio Ferreira, Roger Leblanc, Steven Vanni
Journal: Neuro-Oncology (2022)

Abstract High-grade gliomas remain among the most lethal neoplasms. Nanotechnology aims to Improve drug targeting and efficacy. Here we developed a quadruple nano-model (QNM) that specifically targets pediatric high-grade glioma cells and delivers chemotherapies to the cell nucleus. This carbon dot based QNM were fabricated by covalently attaching two drugs (epirubicin and temozolomide) and two targeting peptides. ShPep-1 peptide binds to the IL-13Rα2 receptors allowing for cellular import while lnPep-1h peptide delivers the DNA damaging drugs to the nucleus. Despite demonstrating the lowest measurable drug content (23.3%), the dual peptide linked QNM induced significantly greater cell death than single peptide linked conjugates suggesting enhanced cell uptake. Greatest effect was observed in glioblastoma (SJ-GBM2) and diffuse intrinsic pontine glioma (NP53) cells with IC50s of approximately 60 nM, 3-6-fold lower than single peptide conjugates. Imaging studies using FITC-conjugated carbon dots confirmed the dual peptide conjugate demonstrated greatest cellular uptake and nuclear localization.
CTNI-04. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS
Authors: Dorsa Sadat Kiaei, Valerie Larouche, Jean-Claude Décarie, Uri Tabori, Cynthia Hawkins, Sarah Lippe, Benjamin Ellezam, Luis H Ospina, Yves Theoret, Leandra Desjardins, Marie-Elaine Metras, Serge Sultan, Edith Cantin, Marie-Eve Routhier, Chantal Mailloux, Marie-claude Bertrand, Maxime Caru, Tara McKeown, Stephanie Vairy, Geneviève Legault, Eric Bouffet, Vijay Ramaswamy, Hallie Coltin, Lucie Lafay-Cousin, Juliette Hukin, Craig Erker, Nada Jabado, Mathieu Dehaes, Sébastien Perreault
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Plexiform neurofibromas (PN) are observed in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial. METHODS This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. Patients received daily oral trametinib (MEK inhibitor) for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method. RESULTS As of May 15, 2022, 46 patients with PN were enrolled in the study and the recruitment was completed for this study arm. Thirty-four completed treatment and were available for analysis. For these patients, the median age was 10.5 years (range 0.7-19.8). The median volume of PN at baseline was 51cm3 (range 2.6 to 487.6). Among the 34 patients, 28 (82.4%) completed 18 cycles as planned. Two patients discontinued due to adverse reaction, three patients refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 16.8 months (range 2.8 to 16.8). Median duration of follow-up was 30.4 months (range 8.2 to 42). A total of 38 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 13.1%. Volumetric assessment demonstrated an overall response rate of 64.7% (22/34 patients), and 65.8% (25/38 PN) of PN showed a decrease of more than 20% in volume. Median volume change was -30% (range -93.5 to 14.3). Thirty-one patients (91.1%) had durable response without progression (lasting ≥ 1 year). After discontinuation of treatment, one patient underwent surgery and three patients resumed MEK inhibitor. CONCLUSION We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib is effective and offers durable response.
INNV-31. PROTECT: PROCARBAZINE, LOMUSTINE, AND VINCRISTINE VERSUS TEMOZOLAMIDE IN HIGH-RISK, LOW-GRADE GLIOMAS: A RETROSPECTIVE COHORT STUDY
Authors: Jason Jia, Bader Alshamsan, Cristina Andronic, Francesco Fazzari, Jennifer Leigh, Hely Shah, Terry Ng
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Low-grade gliomas (LGG), specifically WHO grade 2 diffuse astrocytoma and oligodendroglioma, are increasingly considered for adjuvant chemotherapy with high-risk features (age ≥ 40y or subtotal resection). This is based on prospective studies showing improvement in survival with adjuvant procarbazine, CCNU, vincristine (PCV) or temozolomide (TMZ) in this cohort. Use of PCV or TMZ is variable without published head-to-head comparison. PROTECT is a Canadian multicentre retrospective study aiming to compare overall survival (OS) in high-risk LGGs receiving PCV or TMZ. We are presenting results from The Ottawa Hospital Cancer Centre (TOHCC). METHODS Patients age ≥ 18y with LGG that received PCV or TMZ within 6 months of primary brain tumor resection at TOHCC from 2005 to 2019 were included. The primary outcome is OS. Secondary outcomes include 1)time to progression (TTP), 2)rate of completion of 6 cycles of PCV or TMZ, and 3)rate of hospitalization or death due to chemotherapy-related complications. RESULTS Of 250 cases, 20 patients (11 diffuse astrocytoma, 9 oligodendroglioma) were eligible. IDH status was mutated in 11, wild-type in 1, and unknown in 5 cases. 1p/19q co-deletion was present in 6, non-co-deleted in 1, and unknown in 13 cases. Six patients received PCV, and 14 received TMZ. Hematologic toxicity (CTCAE Grade 1-2) occurred in 3 PCV patients and 0 of 11 of assessable TMZ patients; no severe toxicity was observed. Median follow-up was 64.5 (IQR 42.5–88) months. The median OS and TTP for PCV and TMZ groups were not reached. The 5-year OS and TTP were 75% vs. 100 % (p=0.08) and 83.3% vs 81.3% (p=0.7) respectively. CONCLUSIONS There are insufficient cases and follow-up time to determine OS and TTP amongst patients treated with PCV or TMZ. Hematologic toxicity appears to be more common with PCV. Patient screening and data collection is ongoing at 8 other cancer centres.
RADT-41. IATROGENIC INFLUENCE ON PROGNOSIS OF RADIATION-INDUCED CONTRAST ENHANCEMENTS IN PATIENTS WITH GLIOMA WHO 1-3 FOLLOWING PHOTON AND PROTON RADIOTHERAPY
Authors: Tanja Eichkorn, Jonathan Lischalk, Maximilian Deng, Sandrini Elisabetta, Meixner Eva, Sebastian Regnery, Thomas Held, Julia Bauer, Emanuel Bahn, Harrabi Semi, Hoerner-Rieber Juliane, Herfarth Klaus, Debus Juergen, Koenig Laila
Journal: Neuro-Oncology (2022)

Abstract Radiation-induced contrast enhancement (RICE) is a common side effect following radiotherapy for glioma, but both diagnosis and handling are challenging. Due to the potential risks associated with RICE and its challenges in differentiating RICE from tumor progression, it is critical to better understand how RICE prognosis depends on iatrogenic influence. We identified 99 patients diagnosed with RICE who were previously treated with either photon or proton therapy for World Health Organization (WHO) grade 1-3 primary gliomas. Post-treatment brain MRI-based volumetric analysis and clinical data collection was performed at multiple time points. The most common histologic subtypes were astrocytoma (50%) and oligodendroglioma (46%). In 67%, it was graded WHO grade 2 and in 86% an IDH mutation was present. RICE first occurred after 16 months (range: 1 - 160) in median. At initial RICE occurrence, 39% were misinterpreted as tumor progression. A tumor-specific therapy including chemotherapy or re-irradiation led to a RICE size progression in 86% and 92% of cases, respectively and RICE symptom progression in 57% and 65% of cases, respectively. A RICE-specific therapy such as corticosteroids or Bevacizumab for larger or symptomatic RICE led to a RICE size regression in 81% of cases with symptom stability or regression in 62% of cases. RICE progression went along with a worsening in progression-free survival (p = 0.04). While with chemotherapy and re-irradiation a RICE progression was frequently observed, anti-edematous or anti-VEGF treatment frequently went along with a RICE regression. For RICE, correct diagnosis and treatment decisions are challenging and critical and should be made interdisciplinarily.